Wound healing involves a complex but orderly sequence of cellular events that culminates in the restoration of structural integrity of tissue. The orderly influx of inflammatory cells, proliferation of stromal elements, in-growth of blood vessels, and production of an extra-cellular matrix are essential for rapid and efficient healing. Maximum tissue strength is achieved through the regulated remodeling and maturation of the extra-cellular matrix. Tissue repair is regulated in part by cells at the wound site that control the local production of growth factors, including transforming growth factor beta. Wound healing begins with a repair cascade, which culminates in the formation of new granulation tissue.
Cutaneous ulcers are a common, chronic problem and are primarily developed as pressure (decubital) sores. In addition to causing pain and discomfort and predisposing the patient to superficial and chronic infection, significant costs are associated with the treatment that is often long-term. Chronic ulcers may also arise as a result of chronic steroid therapy for autoimmune disease or atopic dermatitis as well as chemotherapy for cancer. These conditions and their treatment regimens may impair the normal wound healing process and often result in chronic ulcers. While the etiology of pressure sores or ulcers resulting from chronic steroid or chemotherapy may be different, the underlying manifestation is the lack of formation of granulation tissue and re-epithelialization of the defect. Depending on the health and background of the patient, these cutaneous open wounds and ulcers can persist chronically for extended periods of time. Each of these types of cutaneous open wounds and ulcers results in considerable discomfort to the patient and presents a continuing opportunity for even more serious infections or complications to occur. In addition to these common cutaneous open wounds and ulcers, a variety of other skin defects are known to occur in both animals and humans, including lacerations, perforations, wounds which are traumatic in origin, venous stasis ulcers, and other types of lesions.
These types of wounds also occur in other vertebrates such as birds and reptiles. The fundamental pathogenesis of wounds and processes for wound healing is similar for all vertebrates, and therefore the person of ordinary skill will realize that the methods and compositions of the present invention are useful for treating chronic wounds and ulcers in all vertebrates.
By xe2x80x9copen woundxe2x80x9d is meant any injury, which communicates with the atmosphere, by direct exposure. Open wounds include, but are not limited to, decubital ulcers, dehiscence wounds, acral lick dermatitis (acral lick granulomas in animals), lacerations, and wounds that are traumatic in origin. By xe2x80x9culcerxe2x80x9d is meant a break in the continuity of the epidermis with a loss of substance and exposure of underlying tissue. By xe2x80x9cchronic cutaneous open wound or ulcerxe2x80x9d is meant a cutaneous open wound or ulcer, which has shown resistance to completing the healing process. By xe2x80x9cburn woundsxe2x80x9d is meant a surface wound ranging from first to third degree burn and ranging from affecting 1% to 99% body surface area.
The cessation of blood flow to an ischemic lesion can be developed in a slow and gradual form such as in the case of decubitus ulcers and stasis ulcers, or may take place more acutely such as in thermo-radiation and chemical burns. In the absence of nutrition, the rate of fluid delivery of nutrients decreases bringing a progressive impairment in the viability of cells and tissues. This eventually leads to degeneration and death of the tissue and cells in a condition known as necrosis. Necrosis is generally accompanied by bacterial, fungal and/or viral contamination. As further pointed out in the aforementioned patent, treatment of exudative skin wounds with a starch hydrolysate dressing produces a greatly reduced bacteria count of an infected wound and inhibits infection of an uninfected wound. In addition, application of the starch hydrolysate to a wound or ulcer produces a film or semi-permeable membrane which allows edematous liquid to pass through while proteinaceous material is retained within the body, allowing reduction in the volume of exudate in relatively clean condition.
The process of wound healing consists of three phases during which the injured tissue is repaired, regenerated, and new tissue is reorganized into a scar. These three phases are classified as: a) an inflammation phase which begins from day 0 to 3 days, b) a cellular proliferation phase from 3 to 12 days, and c) a remodeling phase from 3 days to about 6 months. In the inflammation phase, inflammatory cells, mostly neutrophils, enter the site of the wound followed by lymphocytes, monocytes, and later macrophages. The neutrophils that are stimulated begin to release proteases and reactive oxygen species into the surrounding medium with potential adverse effects on both the adjacent tissues and the invading microorganisms. The oxygen species known to be released by the neutrophils are superoxide through the action of a plasma membrane-bound NADPH oxidase, hydrogen peroxide formed by action of dismutation of superoxide, and HOCl produced by the action of myeloperoxidase with hydrogen peroxide. The proliferative phase consists of laying down new granulation tissue, and the formation of new blood vessels in the injured area. The fibroblasts, endothelial cells, and epithelial cells migrate in the wound site. These fibroblasts produce the collagen that is necessary for wound repair. In reepithelialization, epithelial cells migrate from the free edges of the tissue across the wound. This event is succeeded by the proliferation of epithelial cells at the periphery of the wound. Research has also shown that reepithelialization is enhanced by the presence of occlusive wound dressings which maintain a moisture barrier. The final phase of wound healing, which is remodeling, is affected by both the replacement of granulation tissue with collagen and elastin fibers and the devascularization of the granulation tissue.
A large variety of treatment and modalities are available for the treatment of wounds and ulcers as described here. These range from applications of antibiotics, occlusive layers, bandages, poultices, mechanical devices that reduce evaporation of water and many others. However, all of these modalities have one drawback in common; they all enhance wound healing by supporting the body mechanisms to heal the wound. Unfortunately, the passive healing process results in much disappointment because the body may have compromised immunity or other body functions that may not work optimally. What is needed is a modality of treatment that will actively regenerate the skin, dermis and epidermis. In the invention described here, the specific composition actively promotes healing by stimulating stem cells that are present even in deep wounds and burns to regenerate the lost tissue.
Stem cells are by definition present in all self-renewing tissues. These cells are believed to be long-lived, have a great potential for cell division and are ultimately responsible for the homeostasis of steady-state tissues. Stem cells are normally slow cycling. They can, however, be induced to enter the proliferative pool in response to certain growth stimuli. When stem cells undergo occasional cell division, they give rise to more rapidly proliferating xe2x80x9ctransient amplifying cellsxe2x80x9d (xe2x80x9cTAxe2x80x9d). Stem cells possess many of the following properties: they are relatively undifferentiated, ultrastructurally and biochemically; they have a large proliferative potential and are responsible for the long term maintenance and regeneration of the tissue; they are normally xe2x80x9cslow-cyclingxe2x80x9d, presumably to conserve their proliferative potential and to minimize DNA errors that could occur during replication; they can be stimulated to proliferate in response to wounding and to certain growth stimuli; they are often located in close proximity to a population of rapidly proliferating cells corresponding to the transient amplifying cells (xe2x80x9cTAxe2x80x9d) in the scheme of (1) stem cell to (2) TA cell to (3) terminally differentiated cell, and they are usually found in well protected, highly vascularized and innervated areas. Positive identification of stem cells has been difficult because, there are few known immunological or biochemical markers specific for epithelial stem cells. Since they are normally xe2x80x9cslow-cyclingxe2x80x9d, they cannot be labeled by single pulse administration of radioactive materials typically used to detect actively proliferating TA cells. The U.S. Pat. No. 5,756,094 to Lavker, et al., describes a method for identification of these cells by labeling these cells continuously to generate label-retaining cells (LRCs). Cotsarelis et al., J. Invest. Dermatol. 1989, 92(3) disclose a method to facilitate detection of LRCs based on the ability of slow-cycling cells to be recruited to proliferate in response to hyperplastic stimuli.
A number of growth factors have been reported to be useful for modulating stem cell activity. For example, cytokines such as Tumor Necrosis Factor (TNF), Epidermal Growth Factor (EGF), Transforming Growth Factor (TGF) and Interleukin-1 (IL-1) are believed to be useful. Because stem cells are normally slow cycling but proliferate rapidly upon inductive stimulation, they may be attractive targets for cytokines such as TNF. EGF has been shown to have broad biological effects. Furthermore, it has been shown to support growth during fetal development and accelerate re-epithelialization during wound healing. TGF-xcex1 has been shown to be involved in the regulation of both growth and differentiation of epithelial cells. IL-1 is known to induce proliferative activity in epidermal cells.
In this invention, an alcoholic extract of ingredients in dried powdered state consisting of Huangqin (baikal skullcap), Huanglian (rhizome of Chinese goldthread or rhizoma coptidis), Huangbai (cortex phellodendri), earthworm (Dilong), Cactus (opuntia ficus indica) in which each of the ingredients is preferably in an amount of about 5%, and in the range of 1.0 to 15% of the final amount of preparation and soybean concentrate as a source of xcex2-sitosterol is used. In the foregoing assertion, efforts have been made to find a suitable palliative and/or curative agent for the treatment of wounds and ulcers from medicinal plants and other natural or synthetic ingredients.
Several herbal products have been proposed for the treatment of wounds and ulcers. The U.S. Pat. No. 6,133,440 to Qiu, et al., provides a rapid and efficient method for the preparation and isolation of biologically active polysaccharides from Aloe, xe2x80x9cImmuno-10xe2x80x9d and the use of the polysaccharides as immunostimulating, immunomodulating and wound healing agents. The U.S. Pat. No. 6,027,728 to Yuen comprises a selection of herbal materials with curative effects combined in a powdered form for application to human skin to accomplish skin regeneration, particularly for application to human skin affected with eczema, psoriasis, allergic reactions, inflammatory rash and the like. The process of application is critical to effectiveness of the present invention. The application of the herbal powder to the skin is intended to cause a temporary inflammation, which removes at least an upper skin layer, with some mild to noticeable discomfort, and causes accelerated skin regeneration so that soft, unaffected skin replaces the scaling and/or lesioned skin. The U.S. Pat. No. 5,693,327 to Shah relates to the preparation and use of compositions for the treatment of skin disorders such as psoriasis, eczema and lichen planus, as well as for the promotion of good health and the alleviation of stress. The compositions are based on extracts from the plants Melia azadirachta and/or Centratherum anthelminthicum. A variety of other herbal extracts may be included, and the compositions may take the form of a cream or ointment based on ghee, or they may be in a powdered form of suitable for preparing decoctions in hot water. The U.S. Pat. No. 5,766,614 to Yong is a new Burn Treatment Composition which provides healing to the skin of people who have received burns or are afflicted with other skin complications that require healing. The inventive device includes effective amounts of Chinese rhubarb; calcium hydroxide; sanguisorba officinalis rhizome; common camphor; coptis chinensis rhizome; phellodendron amurense bark and oldenlandia diffusa roxd. The U.S. Pat. No. 6,126,950 to Bindra, et al., relates to a formulation of herbal cream for cracked heels and palms. It is comprised of a natural wax as an emulsifier, extract of curcuma and the gum of Acacia or Colophonium or Shorea. The gum gives a synergistic effect in binding and healing the skin with natural wound healing herbal extract selected from the aqueous extracts of curcuma, neem and allantonin. This is combined with a wound healing fragrant oil. The natural wound healing herbal extract acts as a humectant and the gum gives a synergistic effect in binding the skin thereby reducing water loss from the skin. The cream spreads evenly and smoothly when applied on the affected parts, and quickens healing, restores natural suppleness and softness and also serves as an antiseptic. The U.S. Pat. No. 5,405,608 to Xu for an invention that relates to a pharmaceutical preparation mainly used for treating thermal injuries of warm-blooded mammals and human. It is composed of 3 to 15% by weight of beeswax and 85 to 97% by weight of sesame oil extract of Huangqin, Huanglian, Huangbai, earthworm and poppy capsule. Scorched in the sesame oil extract, each of Huangqin, Huanglian, Huangbai, earthworm and poppy capsule is in an amount of 2 to 10 weight percent based upon the total weight of sesame oil. This invention also relates to a process for preparing the pharmaceutical preparation and includes as its essential component, beeswax. The present invention does not make use of poppy capsule, nor does it require use of sesame oil or beeswax; the present invention contains Opuntia not included in Xu""s patent and utilizes a different method for the extraction of active ingredients, viz., in alcohol versus high-heat cooking in sesame oil. It is further noteworthy that a significant population is allergic to sesame oil, which is often used as a positive control for measure allergenicity. Also, direct application of poppy capsule extract can lead to many systemic complications because of the narcotic nature of the ingredients of this herb. U.S. Pat. No. 4,837,024 describes compositions which enhance and promote the wound healing process and which comprise suspensions of the fibrous protein, collagen, and of a polysaccharide, namely a glycosaminoglycan. The glycosaminoglycan is one which exhibits chemotaxis for fibroblasts or endothelial cells; the preferred glycosaminoglycans are said to be heparin, heparan sulfate and alginate, although it should be noted that alginate is not in fact a glycosaminoglycan.